Gauging potency of anti-histamines, OTC vs Remeron etc?

[JohnBoy2000]

I shouldn't have to ask this question but, when it comes down to it - how's it done?

Cause I can't find receptor affinity/Ki values for H1, 2 or 3, and short of that, I'm at a loss to understand how potency of by example, a standard OTC anti-histamine like diphenhydramine or promethazine can be compared to the anti-histamine I'm most used to, mirtazapine.

Cause I recently had a piece of surgical stainless steel removed from my jaw and it seems I no longer require the meds I've been taking; a combo of mirtazapine and atomoxetine.

However, it seems there's a little insomnia now without the mirtazapine so, I've been trying to replace it with an OTC anti-histamine.

The pharmacists have basically been telling me, quite specifically that, it'll take about a box of standard OTC anti-histamines to compare to even 15 mg of mirtazapine.

How do they know this so specifically?

If there was a Ki chart of affinities to histamine receptors, like there is for 5HT receptors etc - I'd say, I understand.

But this doesn't exist.

So - how do they know how to compare potencies so accurately?

 

[checktest]

For what it is worth:

Pharmacology of Antihistamines

This article reviews the molecular biology of the interaction of histamine with its H[1] -receptor and describes the concept that H[1] -antihistamines are not receptor antagonists but are inverse ...

www.ncbi.nlm.nih.gov

"The affinity of an H1-antihistamine for H1-receptors is determined in preclinical studies. Desloratadine is the most potent antihistamine (Ki 0.4 nM) followed by levocetirizine (Ki 3 nM) and fexofenadine (Ki 10 nM)"
2nd gen may not be as CNS active as older ones but higher affinity.

Per wiki: Mirtazapine Ki in Nm, as you know

H1

0.14–1.6

Human

[69][67][7]

Perhaps they are judging off of some experience, knowledge or pharmacy databases? Or saying things.

Can use drugbank

Fexofenadine: Uses, Interactions, Mechanism of Action | DrugBank Online

Fexofenadine is a selective H1-antagonist for the symptomatic treatment of seasonal allergic rhinitis and chronic idiopathic urticaria.

www.drugbank.ca

Pubchem

Fexofenadine

Fexofenadine | C32H39NO4 | CID 3348 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

Bindingdb

BindingDB BDBM22874 2-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic acid::2-[4-(1-hydroxy-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}butyl)phenyl]-2-methylpropanoic acid::Allegra::CHEMBL914::Fexofenadine::

Protein-Ligand Binding and Molecular Recognition Database

www.bindingdb.org

Chembl

Compound: CETIRIZINE

Molecule Type: Small molecule, Molecular Formula: C21H25ClN2O3, Molecular Weight: 388.90, Synonyms: Cetirizine;AC-170;Cetiderm

www.ebi.ac.uk

IUPHAR/BPS

cetirizine | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY

The IUPHAR/BPS Guide to Pharmacology. cetirizine ligand page.

www.guidetopharmacology.org

And others. I am certainly not a pharmacist or pharmacology researcher but usually can find some idea. There's likely more science and also a little art in determining and judging for some.

Yeah coming off mirtazapine can definitely mix up sleep for a bit. Some very short term temazepam and cetirizine could be useful. But if you are sleeping more than 4 hours that would be good.

That's great you have done well after the surgery!

 

[Skorpio]

Cetirizine and fexofenadine are both second generation antihistamines. These are substrates for p glycoprotein pumps in the blood brain barrier which remove exogenous compounds. This is why they are considered non drowsy.

Ki values aren't the end all be all in pharmacology. They refer to the affinity of a drug to a given receptor, which is simply how tight it binds. They are useful when comparing the relative affinities of a drug to multiple receptors to see how selective it is. (Ie a lot of over the counter antihistamines have significant affinities for muscarinic acetylcholine receptors).

Now affinity doesn't say what the drug is doing to the receptor. This is the measurement of efficacy. Often values aren't quoted, simply the general effect (agonist, partial agonist, antagonist, inverse agonist) but these refer to the degree of activation of a receptor (inverse agonists silence receptors that have some low level of active activation, even when no ligand is bound, where antagonists have no effect when bound, but prevent agonists from binding).

Both affinity and efficacy are arbitrary measures though. They are measures of either displacement of a labelled ligand (affinity) or activation of a receptor in an assay (efficacy). Due to this, individual numbers vary from assay to assay, and the values should be seen as a way to rank compounds relative to one another. Finally due to the range of results between assays (even ones designed in a similar way) affinity and efficacy numbers shouldn't be compared against one another, rather the rankings of compounds (any good study will have a few for reference) should be compared for more valid results.

You should look for an antihistamine with the least antimuscarinic activity, that will allow for higher doses to be reached without side effects. Unfortunately a lot of otc antihistamines are significantly antimuscarinic.

 

[checktest]

I forgot to mention those were 2nd and '3rd' generation antihistamines while it was mentioned above, as well as the difference. Loratadine is a Pgp substrate as well.

Thanks for the pharmacology coverage skorpio. Biased agonists are something I've been meaning to read up on, with some of those biased opioid agents like oliceridine getting out there.

Frontiers | A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

Between 2000 and 2005 several studies revealed that morphine is more potent and exhibits fewer side effects in beta-arrestin 2 knockout mice. These findings ...

www.frontiersin.org

I happened to use cetirizine when I came off 60 mg mirtazapine because I started getting rashes and allergies way up, and it always made me tired in the past.

Hydroxyzine is an option as well, much less muscarinic vs. doxylamine & diphenhydramine.

 

[Skorpio]

Biased agonism is going to be the next big thing in pharmaceuticals, there are biased ligands in development for pretty much any receptor that recruits beta arrestin (cb1, mu opioid, and beta adrenergic). Also psychadelics function through biased 5ht2a signalling.


Hydroxyzine is great if one can get it. The lack of muscarinic effects plus the light antiserotonergic effects make it a fairly comforting antihistamine for sleep.
Cb1

Characterization of structurally novel G protein biased CB1 agonists: Implications for drug development - PubMed

The human cannabinoid subtype 1 receptor (hCB₁R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB₁R agonists produces unwanted psychotropic effects...

www.ncbi.nlm.nih.gov

Beta adrenergic

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and...

journals.plos.org

Mu

Abuse Potential of Biased Mu Opioid Receptor Agonists - PubMed

G protein-biased mu opioid receptor (GPB-MOR) agonists constitute an emerging class of opioid analgesics. The first-in-class GPB-MOR agonist TRV130 (oliceridine) produces typical opioid-like abuse-related effects in rodents and humans. Although GPB-MOR agonists may be safer than conventional...

www.ncbi.nlm.nih.gov

 

[JohnBoy2000]

Promethazapine is one I know my doctor will write a script for - up to 50 mg I believe?

In contrast to the above mentioned, cetirizine, Hydroxyzine - efficacy as a sleep inducer?

That's great you have done well after the surgery!

Yes, after so much psychiatric orientated treatment (mostly increasing noradrenaline), it became clear there was something else at play.

Tracking things exclusively via timeline, the symptoms emerged following the surgery and implant of the metal, and exacerbated and deteriorated further over the years, slowly, insidiously.

The psych drugs did give me the cognizance to actually consider the situation in depth, and since my insurance covered it, it made sense to just have the removal surgery.


Why could this have caused the issue?

Constituents of the wire are, chromium, nickle, molybdenum.

The latter has one documented case of psychiatric symptom induction, when used as an oral supplement (too much taken).

I can't comment specifically but perhaps being within the blood already, the metal perhaps caused additional symptoms - though no doctor I've met (and there have been many), ever seemed to be aware of those possibly being a cause.

But like I said - purely going on timeline - it just made sense to tend to it.

And HEYPRESTO!! - no more symptoms;
Or vastly reduced. No more anxiety, withdrawal, social symptoms etc.
Well - they're reducing more and more by the day - I assume due to blood clearance.

13 years gone - in the blinking of an eye, living like a dysfunctional bum, a junkie.
Pffff.

But hey at least I've finally got to the bottom to this, cause that elusive answer was really pissing me off!

 

[checktest]

Yeah, I don't believe you'll find many cross-class drug studies (APs, antihistamines, sedating antidepressants) on older drugs with multiple affinity /profile comparisons unless some group had a very particular issue they were studying (or drug, likely isomer promotion).

Promethazine can certainly work as a sedative. Not a clean drug (phenothiazine, pretty much an AP) by any stretch but if you aren't sleeping it can work. Definitely helps with nausea (AP). I took it during migraines. I think some on this board would say it goes better with codeine and actual opioids however.

Hey, if it works it works. I think some people go their entire lives looking for an answer or without one they feel fits. There may be none (a specific incident) or no particular instigating factor within our realm of knowledge.

Sounds like some time to enjoy and explore. Take it easy out there.

 

[Hodor]

Promethazapine is one I know my doctor will write a script for - up to 50 mg I believe?

In contrast to the above mentioned, cetirizine, Hydroxyzine - efficacy as a sleep inducer?

As checktest said, promethazine is a very "dirty" drug, meaning it blocks all kinds of receptors across the board, including dopaminergic ones. Unless the mirtazapine was giving you problems, I'd say there is little reason to switch one for the other.

Ceterizine is a second-generation antihistamine, and as such it has significantly reduced effects in the central nervous system (meaning it retains its effects against allergies, but causes significantly less sedation, making it much less useful as a sleep aid).

Hydroxyzine and diphenhydramine are pretty much the go-to drugs when it comes to OTC insomnia relief. They reliably produce sedation by blocking histamine receptors... IMO, diphenhydramine is the better choice, as it has a "cleaner" pharmacology (greater selectivity for blocking histamine receptors) though.

But no, you won't have to eat a whole box of diphenhydramine to match a single 15 mg dose of mirtazapine.
IME 15 mg of mirtazapine equals roughly 50 mg of diphenhydramine or 25 mg of hydroxyzine... you sure as hell don't want to start off by taking an entire strip of these, because despite being OTC, antihistamines tend to have strong anticholinergic effects, meaning that an overdose results in delirium (as well as cardiac arrythmias, dry mouth, not being able to urinate, and a slew of other unpleasant symptoms).

 

[JohnBoy2000]

I got my doc to script promethazine and horsed 75 mg of it last night.

Nothing.
Plus I feel like shit today.

Not sure of the explanation but, mirtazapine just worked for sleep, where this doesn't.
And yes there was an issue with mirtazapine - undesirable psychoactive component and affect on personality.

Hydroxyzine, diphenhydramine - so, do I need to drink a half bottle of cough syrup each night now?
I can't find either listed as included on anything other than cough syrup.

 

[checktest]

Did you taper the mirtazapine / how many days have you been off it? For some it can be a bear to get off of. (There is a recommendation to taper it and not just drop cold turkey from 60mg....like I did...)

Mirtazapine does have its own unique profile (I mean mianserin but still) and potency that might not be simply replaced. Besides 5-ht2a, h1, adrenergic effects (even compared to tricyclics. )

Magnesium, glycine, valerian root, chamomile, melatonin are some OTC options in addition. Well unless you are in South Africa or some place where melatonin is controlled.

My insomnia got worse a week after I quit mirtazapine. I have had insomnia since being a little kid but it did cross my four-hour barrier for sleep disruption.

Short term trazodone, doxepin, or benzos are possibilities if the antihistamine didn't work over a few days. I would avoid going too high on the diphenhydramine and such- any trip report would tell you why, how the drug changes.

An NP gave me zolpidem which didn't work for me(5 mg, 10, 10 + 10 mid wake, 30) but some temazepam and time did. I didn't want to take some seroquel I had on hand, or lorazepam, but they can be possibilities.

In the longer term it can be useful to reestablish sleep hygiene, as it can be easy to rely on sleep medicines and then forget good habits or fall into the caffeine trap. I don't mean you specifically but in general it can be possible to get used to not having to prepare (without overthinking) a sleep state.

I mean there are hypomanic and manic mirtazapine withdrawal shifts, so definitely some activity there.

Short term use for tapering is also a possibility.

Edit: CBD
I don't like benzos personally because I find I get more depressed on them but they can serve a purpose, sometimes. They didn't work well for me in the past when I was more depressed but that's another story.

 

[Hodor]

Hydroxyzine, diphenhydramine - so, do I need to drink a half bottle of cough syrup each night now?
I can't find either listed as included on anything other than cough syrup.

Diphenhydramine is the active ingredient in Benadryl, which is arguably America's most popular sleep aid ?. And yes, it is available in tablet form. If you're in a location where they don't have the tablets, just ask the pharmacist for generic diphenhydramine.

 

[Meth novice 79]

I don’t know why doctors are so casual about antihistamines, even the OTC ones here are dangerous

Few years ago now I was using them for sleep.
I’ll admit I’d become a little dependent on them to knock me out and was using too much but on day I just randomly started going blind in one eye temporarily, I’d lose feeling/sensation to my shoulders and arms and my vascular issues started out of the blue.
I wenr to my doc who sent me to emerg, my BP was thru the roof, heart rate insane and no one could explain it.
They tested me for lesions on the brain, lukemia, lupus all came back clear.

I mentioned the misuse of phenergan and was brushed off. At this stage I was using no illicit drugs at all but I don’t think they believed that

So I went home and stopped taking the anti histamines and now 8 years later the only symptom left is my vascular condition.

That shits evil